Jagadish Sundaramurthi did Ph.D. on Vaccinology in the National Institute for Research in Tuberculosis (University of Madras), Chennai. He prioritized epitopes using sequence and structure-based methods and rationally modified a few of the prioritized HIV epitopes and demonstrated stronger immune response in vitro for modified epitopes than the respective wild type epitopes against HIV-1. His findings have relevance for rational vaccine design for HIV and other infectious diseases. Further, he analyzed complete genome of Mycobacterium tuberculosis for the prioritization of antigenic proteins and identified epitopes with potential for vaccine design against TB.
During his postdoctoral research in NIRT, India, Jagadish involved in the analysis of Whole Genome Sequences of Mycobacterium tuberculosis that revealed novel drug resistant mutations in M. tuberculosis from India that highlighted the challenges in rapid diagnosis of drug-resistant tuberculosis (DR-TB) in India and suggested the need for region-specific diagnostics for DR-TB. Jagadish contributed in determining the potential repurposing nature of two of the known drugs, lymecycline and cefpodoxime for both drug-sensitive and DR-TB, and developed TBDRUGS database. Further, during the same tenure, Jagadish contributed in the identification of broadly neutralizing antibodies (bNAbs) and bNAbs-specific conformational epitopes against HIV-1. His present research in the Stanford University, California, USA, is aimed at contributing in the further understanding of transmitted drug resistance in HIV-1 with potential application for rational decision making for the treatment of HIV/AIDS and expanding the Stanford HIV Drug Resistance Database that can form the basis for developing rapid diagnostics of drug resistant HIV-1.
Jagadish started his research career in 2001 with an objective to understand the dynamics of HIV coreceptor expression and their natural ligands, chemokines in vivo with a long-term objective to develop chemokine receptor antagonists as drugs. He observed higher amounts of MIP-1alpha, MIP-1beta and RANTES and decreased levels of HIV coreceptors (CCR5 and CXCR4) in HIV-1-positive individuals than healthy volunteers from South India; further, he also reported high rate of hepatitis coinfection in HIV infected individuals of South India which advocated for the early diagnosis of hepatitis viruses in HIV positive person in South India; Jagadish carried out these two research programs in the Division of HIV/AIDS, Tuberculosis Research Centre (TRC, Chennai); these two findings formed his thesis for the award of the degree, M.Phil. by the University of Madras.
Honors & Awards
Bright Star Award, Malaria Genomics and Public Health (EMBO Global Exchange Lecture Course) (29th Jan –11th Feb 2017)
Travel Grant, Malaria Genomics and Public Health (EMBO Global Exchange Lecture Course) (29th Jan –11th Feb 2017)
Fellowship for PG Dip. in Bioinformatics, Department of Biotechnology (DBT), Government of India (2003)
National Eligibility Test (NET) in Life Sciences, Council of Scientific & Industrial Research and University Grants Commission, Government of India (2003)
Bachelor of Science, University Of Madras (2000)
Master of Science, University Of Madras (2011)
Master of Philosophy, University Of Madras (2004)
Doctor of Philosophy, University Of Madras (2015)
Hepatitis B or hepatitis C co-infection in individuals infected with human immunodeficiency virus and effect of anti-tuberculosis drugs on liver function.
Journal of postgraduate medicine
; 52 (2): 92–96
Tuberculosis (TB) and hepatitis are the two common co-infections in patients infected with human immunodeficiency virus (HIV). Anti-tuberculosis treatment (ATT) may have an effect on the liver enzymes in these co-infected HIV patients.To determine the prevalence of Hepatitis B and C virus coinfection in HIV infected patients in Tamilnadu and assess effects of anti-tuberculosis drugs on their liver function.HIV positive subjects referred to the Tuberculosis Research Centre, Chennai.All HIV infected patients referred to the Tuberculosis Research centre, from March 2000 to May 2004, were screened for Hepatitis B surface antigen (HBsAg) & Hepatitis C virus (HCV) antibodies by enzyme linked immunoabsorbent assay (ELISA). HIV infection was confirmed using two rapid tests and one ELISA. Patients were given either short-course anti-tuberculosis treatment or preventive therapy for tuberculosis, depending on the presence or absence of active TB, if their baseline liver functions were within normal limits. None of these patients were on antiretroviral therapy during the study period.Paired t-test was used to find the significance between baseline and end of treatment liver enzymes levels, while logistic regression was done for assessing various associations.Of the 951 HIV-infected patients, 61 patients (6.4%) were HBsAg positive, 20 (2.1%) had demonstrable anti HCV antibodies in their blood. Serial estimation of liver enzymes in 140 HIV patients (81 being co-infected with either HBV or HCV) showed that 95% did not develop any liver toxicity while they were on anti-tuberculosis treatment or prophylaxis.The prevalence of hepatitis B and C coinfection was fairly high in this largely heterosexually infected population supporting the use of more careful screening for these viruses in HIV positive persons in this region. Anti-tuberculosis therapy as well as TB preventive therapy can be safely employed in HIV and hepatitis coinfected patients, if baseline liver function tests are within normal limits.
View details for PubMedID 16679670
Mapping of Neutralizing Antibody Epitopes on the Envelope of Viruses Obtained from Plasma Samples Exhibiting Broad Cross-Clade Neutralization Potential Against HIV-1.
AIDS research and human retroviruses
2019; 35 (2): 169–84
Several broadly neutralizing antibodies (bNAbs) that can target HIV strains with large degrees of variability have recently been identified. However, efforts to induce synthesis of such bNAbs that can protect against HIV infection have not met with much success. Identification of specific epitopes encoded in the HIV-1 envelope (Env) that can direct the host to synthesize bNAbs remains a challenge. In a previous study, we identified 12 antiretroviral therapy-naive HIV-1-infected individuals whose plasma exhibited broad cross-clade neutralization property against different clades of HIV-1. In this study, we sequenced the full-length HIV-1 gp160 from 11 of these individuals and analyzed the sequences to identify bNAb epitopes. We identified critical residues in the viral envelopes that contribute to the formation of conformational epitopes and possibly induce the production of bNAbs, using in silico methods. We found that many of the sequences had conserved glycans at positions N160 (10/11) and N332 (9/11), which are known to be critical for the binding of PG9/PG16-like and PGT128-like bNAbs, respectively. We also observed conservation of critical glycans at positions N234 and N276 critical for the interaction with CD4 binding site bNAbs in 8/11 and 11/11 sequences, respectively. We modeled the three-dimensional structure of the 11 HIV-1 envelopes and found that though each had structural differences, the critical residues were mostly present on the surface of the Env structures. The identified critical residues are proposed as candidates for further evaluation as bNAb epitopes.
View details for DOI 10.1089/AID.2018.0224
View details for PubMedID 30328700
Evidence for Highly Variable, Region-Specific Patterns of T-Cell Epitope Mutations Accumulating in Mycobacterium tuberculosis Strains.
Frontiers in immunology
2019; 10: 195
Vaccines that confer protection through induction of adaptive T-cell immunity rely on understanding T-cell epitope (TCE) evolution induced by immune escape. This is poorly understood in tuberculosis (TB), an ancient, chronic disease, where CD4 T-cell immunity is of recognized importance. We probed 905 functionally validated, curated human CD4 T cell epitopes in 79 Mycobacterium tuberculosis (Mtb) whole genomes from India. This screen resulted in identifying 64 mutated epitopes in these strains initially using a computational pipeline and subsequently verified by single nucleotide polymorphism (SNP) analysis. SNP based phylogeny revealed the 79 Mtb strains to cluster to East African Indian (EAI), Central Asian Strain (CAS), and Beijing (BEI) lineages. Eighty-nine percent of the mutated T-cell epitopes (mTCEs) identified in the 79 Mtb strains from India has not previously been reported. These mTCEs were encoded by genes with high nucleotide diversity scores including seven mTCEs encoded by six antigens in the top 10% of rapidly divergent Mtb genes encoded by these strains. Using a T cell functional assay readout, we demonstrate 62% of mTCEs tested to significantly alter CD4 T-cell IFNγ and/or IL2 secretion with associated changes in predicted HLA-DR binding affinity: the gain of function mutations displayed higher predicted HLA-DR binding affinity and conversely mutations resulting in loss of function displayed lower predicted HLA-DR binding affinity. Most mutated antigens belonged to the cell wall/cell processes, and, intermediary metabolism and respiration families though all known Mtb proteins encoded mutations. Analysis of the mTCEs in an SNP database of 5,310 global Mtb strains identified 82% mTCEs to be significantly more prevalent in Mtb strains isolated from India, including 36 mTCEs identified exclusively in strains from India. These epitopes had a significantly higher predicted binding affinity to HLA-DR alleles that were highly prevalent in India compared to HLA-DR alleles rare in India, highlighting HLA-DR maybe an important driver of these mutations. This first evidence of region-specific TCE mutations potentially employed by Mtb to escape host immunity has important implications for TB vaccine design.
View details for DOI 10.3389/fimmu.2019.00195
View details for PubMedID 30814998
View details for PubMedCentralID PMC6381025
Antibacterial activity of flavonoid isolated from Trianthema decandra against Pseudomonas aeruginosa and molecular docking study of FabZ.
2018; 121: 87–92
The natural product flavonoid demonstrates an extensive sort of pharmacological properties including antimicrobial activity. Although its Pseudomonas aeruginosa inhibition has been discovered, no target for action against flavonoid has been revealed to date. The anti - P. aeruginosa activity of the 2 - (3', 4' dihydroxy-phenyl) - 3, 5, 7-trihydroxy-chromen-4-one isolated from T. decandra was evaluated by disc diffusion and minimum inhibitory concentration methods. The molecular docking of the flavonoid isolated from T. decandra was carried out using CDOCKER (Discovery Studio 2.0). The flavonoid isolated from T. decandra was found to inhibit the growth of P. aeruginosa and the zone of inhibition was found to be 22 ± 0.04 mm at 20 μg/ml while chloramphenicol showed 23 ± 0.05 mm at 30 μg/ml. P. aeruginosa was found to be the most sensitive to both isolated flavonoid and standard control chloramphenicol with MIC values 39.05 μg/ml and 25 μg/ml respectively. Further, the FAS II β-hydroxyacyl-ACP (FabZ) of P. aeruginosa was found to be a potential target of the flavonoid as it docked in silico effectively. Our work has demonstrated the anti - P. aeruginosa activity of flavonoid isolated from T. decandra and also resulted in the elucidation of a plausible mechanism of action of the isolated flavonoid by inhibiting the FabZ using in silico analysis.
View details for DOI 10.1016/j.micpath.2018.05.016
View details for PubMedID 29763727
- Reply to Lee and Howden. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2018; 66 (1): 160–61
In silico and in vitro screening of FDA-approved drugs for potential repurposing against tuberculosis.
View details for DOI 10.1101/228171
Bioinformatics approach to prioritize known drugs towards repurposing for tuberculosis.
2017; 103: 39–45
New drugs are urgently needed to cure tuberculosis (TB) in a short period of time without causing any adverse effects since currently used drugs for the treatment of multi drug-resistant TB cause several adverse effects with poor success rate. Therefore, we aimed to prioritize known drugs towards repurposing for TB by employing bioinformatics approach in the present study. A total of 1554 FDA approved drugs were obtained from DrugBank. Serine/threonine-protein kinase, pknB (Rv0014c) of Mycobacterium tuberculosis (Mtb) was selected as the drug target since it involves in several vital functions of the Mtb. All of the 1554 drugs were subjected to molecular docking with pknB. Glide and AutoDock Vina were employed using rigid docking followed by induced fit docking protocol for prioritization of drugs. Out of 14 drugs prioritized, six are suggested as high-confident drugs towards repurposing for TB as they were consistently found within top 10 ranks of both methods, and strongly binding in the active site of the pknB. We also found atorvastatin as one of the high-confident drugs, which has already been demonstrated to be active against Mtb under in vitro conditions by other researchers. Therefore, we propose that the prioritized six high-confident drugs as potential candidates for repurposing for TB and suggest for further experimental studies. We also suggest that the bioinformatics procedure we have employed in this study could be effectively applied for prioritization of drugs for other diseases.
View details for DOI 10.1016/j.mehy.2017.04.005
View details for PubMedID 28571806
Mycobacterium tuberculosis Whole Genome Sequences From Southern India Suggest Novel Resistance Mechanisms and the Need for Region-Specific Diagnostics.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
2017; 64 (11): 1494–1501
India is home to 25% of all tuberculosis cases and the second highest number of multidrug resistant cases worldwide. However, little is known about the genetic diversity and resistance determinants of Indian Mycobacterium tuberculosis, particularly for the primary lineages found in India, lineages 1 and 3.We whole genome sequenced 223 randomly selected M. tuberculosis strains from 196 patients within the Tiruvallur and Madurai districts of Tamil Nadu in Southern India. Using comparative genomics, we examined genetic diversity, transmission patterns, and evolution of resistance.Genomic analyses revealed (11) prevalence of strains from lineages 1 and 3, (11) recent transmission of strains among patients from the same treatment centers, (11) emergence of drug resistance within patients over time, (11) resistance gained in an order typical of strains from different lineages and geographies, (11) underperformance of known resistance-conferring mutations to explain phenotypic resistance in Indian strains relative to studies focused on other geographies, and (11) the possibility that resistance arose through mutations not previously implicated in resistance, or through infections with multiple strains that confound genotype-based prediction of resistance.In addition to substantially expanding the genomic perspectives of lineages 1 and 3, sequencing and analysis of M. tuberculosis whole genomes from Southern India highlight challenges of infection control and rapid diagnosis of resistant tuberculosis using current technologies. Further studies are needed to fully explore the complement of diversity and resistance determinants within endemic M. tuberculosis populations.
View details for DOI 10.1093/cid/cix169
View details for PubMedID 28498943
View details for PubMedCentralID PMC5434337
Broad and potent cross clade neutralizing antibodies with multiple specificities in the plasma of HIV-1 subtype C infected individuals.
2017; 7: 46557
Broadly Cross clade Neutralizing (BCN) antibodies are recognized as potential therapeutic tools and leads for the design of a vaccine that can protect human beings against various clades of Human Immunodeficiency Virus (HIV). In the present study, we screened plasma of 88 HIV-1 infected ART naïve individuals for their neutralization potential using a standard panel of 18 pseudoviruses belonging to different subtypes and different levels of neutralization. We identified 12 samples with good breadth of neutralization (neutralized >90% of the viruses). Four of these samples neutralized even the difficult-to-neutralize tier-3 pseudoviruses with great potency (GMT > 600). Analysis of neutralization specificities indicated that four samples had antibodies with multiple epitope binding specificities, viz. CD4-binding site (CD4BS), glycans in the V1/V2 and V3 regions and membrane proximal external region (MPER). Our findings indicate the strong possibility of identifying highly potent bNAbs with known or novel specificities from HIV-1 subtype C infected individuals from India that can be exploited as therapeutic tools or lead molecules for the identification of potential epitopes for design of a protective HIV-1 vaccine.
View details for DOI 10.1038/srep46557
View details for PubMedID 28436427
View details for PubMedCentralID PMC5402285
HLA based selection of epitopes offers a potential window of opportunity for vaccine design against HIV.
2017; 35 (42): 5568–75
The pace of progression to AIDS after HIV infection varies from individual to individual. While some individuals develop AIDS quickly, others are protected from the onset of disease for more than a decade (elite controllers and long term non-progressors). The mechanisms of protection are not yet clearly understood, though various factors including host genetics, immune components and virus attenuation have been elucidated partly. The influence of HLA alleles on HIV-1 infection and disease outcome has been studied extensively. Several HLA alleles are known to be associated with resistance to infection or delayed progression to AIDS after infection. Similarly, certain HLA alleles are reported to be associated with rapid progression to disease. Since HLA alleles influence the outcome of HIV infection differentially, selection of epitopes specifically recognized by protective alleles could serve asa rational means for HIV vaccine design. In this review article, we discuss existing knowledge on HLA alleles and their association with resistance/susceptibility to HIV and its relevance to vaccine design.
View details for DOI 10.1016/j.vaccine.2017.08.070
View details for PubMedID 28888341
- TBDRUGS - Database of drugs for tuberculosis. Tuberculosis (Edinburgh, Scotland) 2016; 100: 69–71
Recent developments in genomics, bioinformatics and drug discovery to combat emerging drug-resistant tuberculosis.
Tuberculosis (Edinburgh, Scotland)
2016; 101: 31–40
Emergence of drug-resistant tuberculosis (DR-TB) is a big challenge in TB control. The delay in diagnosis of DR-TB leads to its increased transmission, and therefore prevalence. Recent developments in genomics have enabled whole genome sequencing (WGS) of Mycobacterium tuberculosis (M. tuberculosis) from 3-day-old liquid culture and directly from uncultured sputa, while new bioinformatics tools facilitate to determine DR mutations rapidly from the resulting sequences. The present drug discovery and development pipeline is filled with candidate drugs which have shown efficacy against DR-TB. Furthermore, some of the FDA-approved drugs are being evaluated for repurposing, and this approach appears promising as several drugs are reported to enhance efficacy of the standard TB drugs, reduce drug tolerance, or modulate the host immune response to control the growth of intracellular M. tuberculosis. Recent developments in genomics and bioinformatics along with new drug discovery collectively have the potential to result in synergistic impact leading to the development of a rapid protocol to determine the drug resistance profile of the infecting strain so as to provide personalized medicine. Hence, in this review, we discuss recent developments in WGS, bioinformatics and drug discovery to perceive how they would transform the management of tuberculosis in a timely manner.
View details for DOI 10.1016/j.tube.2016.08.002
View details for PubMedID 27865394
Docking-based virtual screening of known drugs against murE of Mycobacterium tuberculosis towards repurposing for TB.
2016; 12 (8): 359–67
Repurposing has gained momentum globally and become an alternative avenue for drug discovery because of its better success rate, and reduced cost, time and issues related to safety than the conventional drug discovery process. Several drugs have already been successfully repurposed for other clinical conditions including drug resistant tuberculosis (DR-TB). Though TB can be cured completely with the use of currently available anti-tubercular drugs, emergence of drug resistant strains of Mycobacterium tuberculosis and the huge death toll globally, together necessitate urgently newer and effective drugs for TB. Therefore, we performed virtual screening of 1554 FDA approved drugs against murE, which is essential for peptidoglycan biosynthesis of M. tuberculosis. We used Glide and AutoDock Vina for virtual screening and applied rigid docking algorithm followed by induced fit docking algorithm in order to enhance the quality of the docking prediction and to prioritize drugs for repurposing. We found 17 drugs binding strongly with murE and three of them, namely, lymecycline, acarbose and desmopressin were consistently present within top 10 ranks by both Glide and AutoDock Vina in the induced fit docking algorithm, which strongly indicates that these three drugs are potential candidates for further studies towards repurposing for TB.
View details for DOI 10.6026/97320630012368
View details for PubMedID 28275291
View details for PubMedCentralID PMC5312000
HLA-B*27:05-specific cytotoxic T lymphocyte epitopes in Indian HIV type 1C.
AIDS research and human retroviruses
2013; 29 (1): 47–53
HLA-B*27:05 is one of the widely reported alleles associated with resistance to HIV, while HLA-A24, HLA-B7, HLA-B*07:02, HLA-B*35:01, HLA-B*53:01, and HLA-B40 are reported to be associated with susceptibility to HIV. Using a bioinformatics approach we attempted to predict potential HLA-B*27:05-specific HIV-1C epitopes that do not bind to susceptibility-associated HLA alleles based on our hypothesis that such epitopes have a greater probability of eliciting a protective immune response in the host. A consensus sequence was built for all proteins of Indian clade C virus. Epitopes specific to HLA-B*27:05 were predicted from the consensus sequence using two different bioinformatics methods to enhance the accuracy of the prediction. Epitopes that were also predicted to bind to any of the susceptibility-associated HLA alleles were excluded from the list. The short-listed epitopes were modeled using MODPROPEP to refine the prediction. Fourteen peptides were identified as epitopes by both sequence-based methods and were found to interact strongly with HLA-B*27:05 by molecular modeling studies. Five of the 14 epitopes were previously reported as immunogenic by other researchers, while the remaining nine are novel. The 14 epitopes have been repeatedly identified by three different methods indicating their potential as useful candidates for an effective HIV vaccine.
View details for DOI 10.1089/AID.2011.0374
View details for PubMedID 22924625
Informatics resources for tuberculosis - Towards drug discovery
2012; 92 (2): 133–38
Integration of biological data on gene sequence, genome annotation, gene expression, metabolic pathways, protein structure, drug target prioritization and selection, has resulted in several online bioinformatics databases and tools for Mycobacterium tuberculosis. Alongside there has been a growth in the list of cheminformatics databases for small molecules and tools to facilitate drug discovery. In spite of these efforts there is a noticeable lag in the drug discovery process which is an urgent need in the case of emerging and re-emerging infectious diseases. For example, more than 25 online databases are available freely for tuberculosis and yet these resources have not been exploited optimally. Informatics-centered drug discovery based on the integration and analysis of both bioinformatics and cheminformatics data could fill in the gap and help to accelerate the process of drug discovery. This article aims to review the current standing of developments in tuberculosis-bioinformatics and highlight areas where integration of existing resources could lead to acceleration of drug discovery against tuberculosis. Such an approach could be adapted for other diseases as well.
View details for DOI 10.1016/j.tube.2011.08.006
View details for Web of Science ID 000300619800003
View details for PubMedID 21943870
In silico identification of potential antigenic proteins and promiscuous CTL epitopes in Mycobacterium tuberculosis.
Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases
2012; 12 (6): 1312–18
Cell-mediated immunity is critical for the control of Mycobacterium tuberculosis infection. We hypothesized that those proteins of M. tuberculosis (MTB) that do not have homologs in humans as well as human gut flora, would mount a good antigenic response in man, and employed a bioinformatics approach to identify MTB antigens capable of inducing a robust cell-mediated immune response in humans. In the first step we identified 624 MTB proteins that had no homologs in humans. Comparison of this set of proteins with the proteome of 77 different microbes that comprise the human gut flora narrowed down the list to 180 proteins unique to MTB. Twenty nine of the 180 proteins are known to be associated with dormancy. Since dormancy associated proteins are known to harbor CTL epitopes, we selected four representative unique proteins and subjected them to epitope analysis using ProPred1. Nineteen novel promiscuous epitopes were identified in the four proteins. Population coverage for 7 of the 19 shortlisted epitopes including Rv3852 (58-KPAEAPVSL, 112-VPLIVAVTL, 118-VTLSLLALL and 123-LALLLIRQL), Rv2706c (66-RPLSGVSFL) Rv3466 (8- RIVEVFDAL and 38-RSLERLECL) was >74%. These novel promiscuous epitopes are conserved in other virulent MTB strains, and can therefore be further investigated for their immunological relevance and usefulness as vaccine candidates.
View details for DOI 10.1016/j.meegid.2012.03.023
View details for PubMedID 22484107
Resistance-associated epitopes of HIV-1C-highly probable candidates for a multi-epitope vaccine.
2012; 64 (10): 767–72
Earlier studies have identified a large number of immunogenic epitopes in HIV-1. Efforts are required to prioritize these epitopes in order to identify the best candidates for formulating an effective multi-epitope vaccine for HIV. We modeled 155 known cytotoxic T lymphocyte epitopes of HIV-1 subtype C on the 3D structure of HLA-A*0201, HLA-B*2705, and HLA-B*5101 using MODPROPEP, as these alleles are known to be associated with resistance to HIV/slow progression to AIDS. Thirty-six epitopes were identified to bind to all the three HLA alleles with better binding affinity than the control peptides complexed with each HLA allele but not to any of the HLA alleles reported to be associated with susceptibility to HIV infection/rapid progression to disease. As increase in stability of the epitope-HLA complex results in increased immunogenicity, the short-listed epitopes could be suitable candidates for vaccine development. Twenty of the 36 epitopes were polyfunctional in nature adding to their immunological relevance for vaccine design. Further, 9 of the 20 polyfunctional epitopes were found to bind to all three resistance-associated HLA alleles using an additional method, adding worth to their potential as candidates for a vaccine formulation for HIV-1C.
View details for DOI 10.1007/s00251-012-0635-z
View details for PubMedID 22810271
DDTRP: Database of Drug Targets for Resistant Pathogens.
2011; 7 (2): 98–101
Emergence of drug resistance is a major threat to public health. Many pathogens have developed resistance to most of the existing antibiotics, and multidrug-resistant and extensively drug resistant strains are extremely difficult to treat. This has resulted in an urgent need for novel drugs. We describe a database called 'Database of Drug Targets for Resistant Pathogens' (DDTRP). The database contains information on drugs with reported resistance, their respective targets, metabolic pathways involving these targets, and a list of potential alternate targets for seven pathogens. The database can be accessed freely at http://bmi.icmr.org.in/DDTRP.
View details for PubMedID 21938213
View details for PubMedCentralID PMC3174044
Molecular docking of azole drugs and their analogs on CYP121 of Mycobacterium tuberculosis.
2011; 7 (3): 130–33
The Mycobacterium tuberculosis genome codes for 20 different cytochromes. These cytochromes are involved in the breakdown of recalcitrant pollutants and the synthesis of polyketide antibiotics and other complex macromolecules. It has been demonstrated that CYP121 is essential for viability of the bacterium by gene knock-out and complementation studies. CYP121 could therefore be a probable target for the development of new drugs for TB. It has been widely reported that orthologs of CYP121 in fungi are inhibited by azole drugs. We evaluated whether these azole drugs or their structural analogs could bind to and inhibit CYP121 of M. tuberculosis using molecular docking. Six molecules with known anti-CYP121 activity were selected from literature and PubChem database was searched to identify structural analogs for these inhibitors. Three hundred and fifty seven molecules were identified as structural analogs and used in docking studies. Fifty three molecules were found to be scored better than the azole drugs and five of them were ranked among the top 12 molecules by two different scoring functions. These molecules may be further tested by in vitro experimentation for their activity against CYP121 of M. tuberculosis.
View details for PubMedID 22125383
View details for PubMedCentralID PMC3218315
Cellular immune response to Mycobacterium tuberculosis-specific antigen culture filtrate protein-10 in south India.
Medical microbiology and immunology
2010; 199 (1): 11–25
The Mycobacterium tuberculosis (M. tuberculosis)-specific culture filtrate protein-10 (CFP-10) is highly recognized by M. tuberculosis infected subjects. In the present study, the proliferative response and IFN-gamma secretion was found for C-terminal peptides of the protein (Cfp6(51-70), Cfp7(61-80), Cfp8(71-90), and Cfp9(81-100)). The alleles HLA DRB1 *04 and HLA DRB1 *10 recognized the C-terminal peptides Cfp7, Cfp8, and Cfp9 in HHC. Cfp6 was predominantly recognized by the alleles HLA DRB1 *03 and HLA DRB1 *15 by PTB. The minimal nonameric epitopes from the C-terminal region were CFP-10(56-64) and CFP-10(76-84). These two peptides deserve attention for inclusion in a vaccine against tuberculosis in this region.
View details for DOI 10.1007/s00430-009-0129-2
View details for PubMedID 19902247
Immune response to Mycobacterium tuberculosis specific antigen ESAT-6 among south Indians.
Tuberculosis (Edinburgh, Scotland)
2010; 90 (1): 60–69
The 6-kDa early secreted antigenic target (ESAT-6) is a T-cell antigen recognized by individuals infected with Mycobacterium tuberculosis. The aim of the study was to identify "protective epitopes" of ESAT-6 protein in the south Indian population. Proliferative and Interferon gamma (IFN-gamma) responses to ESAT-6 peptides were studied by flow cytometry and Enzyme linked immunosorbent assay (ELISA). Healthy household contacts (HHC) recognized Esp1 (10/17) and Esp6 (9/17) peptides. Among pulmonary tuberculosis patients (PTB), Esp1 (3/11) and Esp6 (5/11) were recognized. Maximal response (7/10) was found for Esp1 and Esp8 in treated patients (TR). Median values for the responding subjects gave the following results: Esp1 (76pg/ml), Esp6 (64pg/ml), induced IFN-gamma production in HHC; PTB gave low IFN-gamma responses for the peptides. TR responded to the peptides Esp1 (141pg/ml), Esp8 (102pg/ml). The proliferation of CD4 cells was similar in both PTB and TR for all peptides; but HHC showed an increase for Esp1 (p<0.05) and Esp6 (p<0.01). Esp1 (amino acids aa 1-20) and Esp6 (aa 51-70) were the immunogenic peptides recognized by the alleles HLA DRB1*04 and HLA DRB1*10 among HHC. But the association of the alleles with ESAT-6 peptide presentation needs to be confirmed in a large cohort of subjects. We speculate that ESAT-6 can be used along with other immune-eliciting proteins for vaccine design strategies in south Indian population.
View details for DOI 10.1016/j.tube.2009.10.003
View details for PubMedID 19944647
Immunological and proteomic analysis of preparative isoelectric focusing separated culture filtrate antigens of Mycobacterium tuberculosis.
Experimental and molecular pathology
2010; 88 (1): 156–62
Isolation of the secreted proteins and studying the immune response they induce is an essential prerequisite for understanding the pathogenesis of M. tuberculosis. In this study, preparative liquid-phase isoelectric focusing was used for the separation of culture filtrate protein (CFP) of M. tuberculosis. This procedure resolved culture filtrate proteins into 20 fractions with a pI range of 2.59 to 12.9. These 20 fractions were subjected to immunological analysis in healthy laboratory volunteers from our endemic area. Eleven fractions (Fractions 5, 6, 7, 8, 9, 10, 11, 13, 15, 16, and 19) showed increased interferon gamma (IFN-gamma) secretion and 5 fractions induced increased proliferative response, when compared to unfractionated CFP. In the 11 fractions which showed increased IFN-gamma secretion, mass spectrometric analysis identified 19 different proteins. Apart from the already reported immunodominant antigens like FbpB, CFP-10 and ESAT-6, two new T cell antigens (AcpM and PpiA) were also identified in the immunologically active fractions. Immunoinformatic analysis showed that PpiA was predicted to bind more number of class I and class II HLA alleles compared with the immunodominant ESAT-6 and CFP-10. Population coverage calculations also showed that PpiA protein (85%) had a higher population coverage compared with ESAT-6 (79%) and CFP-10 (77%). This result shows that the PpiA protein has a potential to be a novel T cell antigen.
View details for DOI 10.1016/j.yexmp.2009.11.008
View details for PubMedID 19944092
Prevalence and pattern of cross-reacting antibodies to HIV in patients with tuberculosis.
AIDS research and human retroviruses
2008; 24 (7): 941–46
In many countries, HIV testing among tuberculosis (TB) patients is recommended so that both infections are appropriately treated. Cross-reacting antibodies to HIV antigens have been reported for several conditions, including TB, leprosy, malaria, and rheumatoid arthritis. To study the pattern and prevalence of cross-reacting antibodies to HIV antigens, we examined sera from 153 HIV-negative TB patients and 40 healthy individuals in Chennai, south India. We also studied the differences in cross-reactivity of various HIV antigens using two different Western blot kits. Of the 153 samples studied, 80 were tested using HIV Western blot and 73 were tested using INNOLIA. Most patients in the study had concordantly negative ELISA and rapid tests, and no subject had a positive Western blot. However, seven TB patients had antibodies that cross-reacted with HIV antigens, giving rise to an indeterminate result. While p51/55 was the most frequently recognized antigen in the Western blot assay, antibodies to sgp120 was most frequently identified in INNOLIA. Sequence similarities between the two organisms could be responsible for eliciting cross-reacting antibodies, since a few related epitopes were identified in HIV and Mycobacterium. These findings could have potential implications for the development of diagnostics and vaccines.
View details for DOI 10.1089/aid.2007.0211
View details for PubMedID 18593340
Short communication: Influence of active tuberculosis on chemokine and chemokine receptor expression in HIV-infected persons.
AIDS research and human retroviruses
2005; 21 (12): 997–1002
Tuberculosis (TB) is the major opportunistic infection of HIV-1-infected patients in developing countries. Concurrent infection with TB results in immune cells having enhanced susceptibility to HIV-1 infection, which facilitates entry and replication of the virus. Cumulative data from earlier studies indicate that TB provides a milieu of continuous cellular activation and irregularities in cytokine and chemokine circuits that favor viral replication and disease progression. To better understand the interaction of the host with HIV-1 during active tuberculosis, we investigated in vivo expression of the HIV-1 coreceptors, CCR5 and CXCR4, and circulating levels of the inhibitory beta-chemokines, macrophage inflammatory protein-1-alpha (MIP-1alpha), macrophage inflammatory protein-1-beta (MIP-1beta), and regulated upon activation T cell expressed and secreted (RANTES), in HIV-positive individuals with and without active pulmonary tuberculosis. We found a significant decrease from normal in the fraction of CD4+ T cells expressing CCR5 and CXCR4 in individuals infected with HIV. However, CCR5 and CXCR4 expression did not differ significantly between HIV patients with and without tuberculosis. Higher amounts of MIP-1alpha, MIP-1beta, and RANTES were detected in plasma of HIV-1-positive individuals, particularly those with dual infection, although the increase was not found to be statistically significant.
View details for DOI 10.1089/aid.2005.21.997
View details for PubMedID 16379602